It is fundamentally important to understand how human innate immune cells respond to pathogens because these cells are frequently the first line of defense against infection. Recent gene expression profiling studies have shown that pathogen exposure causes changes in the gene expression programs of dendritic cells and macrophages, but have not revealed how these gene expression programs are regulated. With a sequenced human genome and advanced genome-wide analytical technologies, it is possible to begin mapping the transcriptional regulatory networks that control the host cell response to infection by priority pathogens. Such information would allow us to discover precisely how pathogens perturb host cell gene expression and might suggest new strategies for pathogen control. We propose to use newly developed experimental and computational technologies to begin mapping the transcriptional regulatory networks that control the response of innate immune cells to pathogen exposure. To accomplish this, we propose to; 1) identify the genomic targets of key transcriptional regulators in human macrophages and dendritic cells; 2) deduce the transcriptional regulatory networks that regulate macrophage and dendritic cell gene expression programs using a combination of genome-wide location and expression data; 3) discover how the transcriptional regulatory networks of macrophages and dendritic cells are modified when these cells are exposed to priority pathogens.